P707: DOSE MODIFICATION DYNAMICS OF PONATINIB IN PATIENTS WITH CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CP-CML) FROM THE PACE AND OPTIC TRIALS
Authors: J. Apperley, H. Kantarjian, M. Deininger, E. Abruzzese, J. Cortes, C. Chuah, D. J. DeAngelo, J. DiPersio, A. Hochhaus, J. Lipton, F. Nicolini, J. Pinilla-Ibarz, D. Rea, G. Rosti, P. Rousselot, M. Mauro, N. Shah, M. Talpaz, A. Vorog, X. Ren, E. Jabbour
Journal: HemaSphere (2022)

Background: Ponatinib, a potent oral, third-generation tyrosine kinase inhibitor (TKI), is FDA approved for treatment of patients with relapsed/refractory CML. In the pivotal Phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial (NCT01207440), patients with resistant/intolerant CP-CML demonstrated deep, lasting responses to ponatinib 45 mg once daily. The Phase 2 OPTIC (Optimizing Ponatinib Treatment in CP-CML) trial (NCT02467270) prospectively evaluated a response-based dose-reduction strategy in an attempt to optimize the dose schedule of ponatinib in patients with CP-CML resistant to second-generation (2G) BCR::ABL1 TKI therapy or with a T315I mutation. Aims: Since the unique dosing strategies in the PACE and OPTIC trials provide the opportunity to closely evaluate the dose and schedule of ponatinib, we conducted an in-depth analysis of dosing dynamics between the 2 trials and compare efficacy and safety outcomes. Methods: Adults with resistant/intolerant CP-CML from the PACE and OPTIC trials were enrolled. In PACE, patients received an initial dose of ponatinib 45 mg once daily, in OPTIC, patients were randomly assigned (1:1:1) to an initial oral dose of ponatinib 45 mg, 30 mg, or 15 mg once daily. In PACE, proactive dose reductions were mandated in ≈2 years from initiation of first patient (in 2013) as arterial occlusive events (AOEs) emerged as notable adverse events (AEs). OPTIC was designed to incorporate a mandatory response-based dose-reduction strategy; patients in the 45-mg and 30-mg cohorts in OPTIC achieving ≤1% BCR::ABL1IS reduced their dose to 15 mg once daily; doses also were reduced to manage AEs. This analysis includes data from patients with CP-CML in PACE and from the 45-mg starting dose cohort in OPTIC. Efficacy outcomes include ≤1% BCR::ABL1IS, progression-free survival (PFS), and overall survival (OS). Safety outcomes include treatment-emergent adverse events (TEAEs) and treatment-emergent AOE (TE-AOE) rates. Results: Together, 364 patients with CP-CML had ≥1 prior 2G TKI or had a T315I mutation and received a starting dose of ponatinib 45 mg (PACE, n=270; OPTIC, n=94). Percentages of patients receiving ≥2 or ≥3 prior TKIs were 93% and 60% in PACE and 99% and 53% in OPTIC, respectively. Percentages of patients with vascular disorders were 44% in PACE and 32% in OPTIC. Median follow-up was 57 months (PACE) and 32 months (OPTIC). ≤1% BCR::ABL1IS response by 24 months was 52% in PACE and 56% in OPTIC, 2-year PFS was 68% in PACE and 80% in OPTIC, and 2-year OS was 86% in PACE and 91% in OPTIC. Median time to ≤1% BCR::ABL1IS response was 5.6 months in PACE and 6 months in OPTIC. Median duration of response was not reached in either trial. Median time to dose reduction for AEs was 2.85 months in PACE and 3.64 months in OPTIC and dose reductions due to AEs occurred in 82% of patients in PACE and 46% in OPTIC. Median time on therapy was 12.6 months in PACE and 19.5 months in OPTIC. Per 100-patient years, exposure-adjusted TE-AOEs were 15.8 events at 0 to <1 year in PACE and 7.6 events at 0 to <1 year in OPTIC. Individual dosing dynamics by safety and efficacy will be presented. Summary/Conclusion: The response-based dose-reduction strategy in OPTIC resulted in comparable or better efficacy outcomes, fewer dose reductions related to AEs, fewer exposure-adjusted TE-AOEs, and longer median time on therapy compared with PACE. These results further demonstrate the benefit of the response-based dosing regimen used in OPTIC. This abstract is an encore from the American Society of Hematology 2021 Annual Meeting.